ARHGEF28

protein-coding

Rho guanine nucleotide exchange factor 28, the group of Dbl family Rho GEFs

Gene summary

This gene encodes a member of the Rho guanine nucleotide exchange factor family. The encoded protein interacts with low molecular weight neurofilament mRNA and may be involved in the formation of amyotrophic lateral sclerosis neurofilament aggregates. Alternate splicing results in multiple transcript variants.[provided by RefSeq, Apr 2010]

MANE transcript

NM_001177693.2

Inheritance

SD, AD, AR

ClinVar variants

U:280B:94

Top phenotype

ARHGEF28-related disorder

gnomAD constraint

pLI —, LoF o/e 0.55

Max pathogenic AF

—

Genomic locus

chr5:73,626,158-73,941,993

External References & Databases

Ensembl (ENSG00000214944)

Transcript & Mutation Effects

hg38 • Region Span ~315.8 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

amyotrophic lateral sclerosisLIMITED

Inheritance Pattern: SD

Disease ID:MONDO:0004976

Submitter: ClinGen

*ARHGEF28* encodes a multidomain protein with guanine nucleotide exchange factor (GEF) activity. Its normal function and the potential mechanism of pathogenicity are so far unclear. *ARHGEF28* was first reported in relation to amyotrophic lateral sclerosis in 2013 (Droppelmann et al., PMID: 23286752). The gene was curated under a semidominant inheritance model due to limited genetic evidence and the presence of both autosomal dominant and autosomal recessive inheritance classifications in GenCC. Ten variants that have been reported in 13 probands in four publications (PMIDs: 23286752, 24712971, 27154192, 31060816) are included in this curation. For nine of these variants, lack of information on testing for variants in other potentially disease-causing genes or the presence of such variants led to a score of 0 points. A predicted splice donor site variant in two probands was scored 0.5 points each due to very limited prior testing. This gene-disease relationship is also supported by expression and protein-protein interaction evidence. ARHGEF28 is expressed in the brain and spinal cord (PMID: 19488899) and forms cytoplasmic inclusions in motor neurons of fALS and sALS patients, but not in normal controls (PMID: 22835604). A split-ubiquitin assay in yeast showed that ARHGEF28 interacts directly with TARDBP (PMID: 32764283). In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the ClinGen ALS GCEP on March 28, 2024 (SOP Version 10).

amyotrophic lateral sclerosisMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0004976

Submitter: Genomics England PanelApp

amyotrophic lateral sclerosisMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0004976

Submitter: Genomics England PanelApp

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ARHGEF28 variants in ClinVar

4 Conditions Cataloged

not specifiedTotal: 250

ARHGEF28-related disorderTotal: 127

not providedTotal: 42

Meniere diseaseTotal: 5

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001177693.2. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			2 clinvar	49 clinvar	6 clinvar	57
missense			268 clinvar	35 clinvar	4 clinvar	307
nonsense						0
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)			10 clinvar			10
Total	0	0	280	84	10	374

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 32 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001177693.2	RefSeq	NP_001171164.1	35	MANE Select
ENST00000513042.7	Ensembl	ENSP00000441436.1	35	MANE Select
NM_001080479.3	RefSeq	NP_001073948.2	36	Standard
NM_001244364.2	RefSeq	NP_001231293.1	28	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
arhgef28a	Danio rerio	Structure: fast muscle cell Quality: disorganized abnormal

Gene / Model

Organism

Observed Phenotype

arhgef28a

Danio rerio

Structure: fast muscle cell

Quality: disorganized

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Developmental Biology
EPH-Ephrin signaling
EPHB-mediated forward signaling
Axon guidance
Signaling events mediated by focal adhesion kinase

Biological Process

cell differentiation
regulation of Rho protein signal transduction
intracellular signal transduction
ephrin receptor signaling pathway

Molecular Function

RNA binding
guanyl-nucleotide exchange factor activity
Rho guanyl-nucleotide exchange factor activity
metal ion binding

Cellular Component

cytosol
plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000545377
Coding exons: 36
Length: 315836
Individuals with no LoFs: 124544
Homozygous LoFs: 1
Heterozygous LoFs: 118
Defined: 124663
p: 0.000477

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.734	823	884	0.931	0.0000485	11235
Missense (PolyPhen)		200	254.12	0.78702		3426
Synonymous	1.61	313	351	0.890	0.0000209	3275
Loss of Function	3.83	47	85.1	0.552	0.00000435	1083

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00046	0.00045	rare
Latino/Admixed American	0.00056	0.00055	rare
Ashkenazi Jewish	0.00020	0.00020	rare
East Asian	0.00063	0.00061	rare
Finnish	0.00014	0.00014	rare
European (Non-Finnish)	0.00036	0.00035	rare
South Asian	0.0012	0.0012	notable
Other	0.00034	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Functions as a RHOA-specific guanine nucleotide exchange factor regulating signaling pathways downstream of integrins and growth factor receptors. Functions in axonal branching, synapse formation and dendritic morphogenesis. Functions also in focal adhesion formation, cell motility and B-lymphocytes activation. May regulate NEFL expression and aggregation and play a role in apoptosis (By similarity). {ECO:0000250}.;

Intolerance Scores

RVIS EVS: -0.27
RVIS percentile EVS: 34.32

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	High	High	High
Primary Immunodeficiency	High	High	High
Cancer	High	High	High